Alzheimer's Curbed By Promising New Drug

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Main Category: Alzheimer's / Dementia
Also Included In: Neurology / Neuroscience;  Seniors / Aging;  Parkinson's Disease
Article Date: 30 Jul 2008 - 3:00 PDT

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A new drug that has completed phase 2 trials in the UK and Singapore is being hailed as a major breakthrough in the treatment of Alzheimer's, as it appeared to slow the progress of the disease by as much as 81 per cent over a year, compared to placebo. Methylthioninium chloride (MTC) blocks the accumulation of tau protein tangles inside brain cells, one of the principal characteristics of the disease that was originally discovered by Alois Alzheimer 100 years ago.

The results of the trial, which was led by Claude M Wischik, Professor in Mental Health, University of Aberdeen, UK, and Chairman, TauRx Therapeutics, Singapore, were presented in Chicago yesterday, 29th July, at the Alzheimer's Association International Conference on Alzheimer's Disease (ICAD) 2008.

Wischik said in a press statement that:

"This is an unprecedented result in the treatment of Alzheimer's disease. We have demonstrated for the first time that it may possible to arrest the progression of this disease by targeting the tangles which are highly correlated with the disease."

Alzheimer's is thought to have two telltale signs: the build up of amyloid protein plaques around brain cells, and the build up of brain lesions or neurofibrillary tangles of tau protein that accumulate inside brain cells. Together these destroy brain cells and connections between them, especially in parts of the brain that are important for memory.

Previous research has shown that progress of Alzheimer's is linked to build up of tau protein tangles inside brain cells, and that the tangles start appearing long before the symptoms are clinically visible.

Wischik and his team have been working on tau tangles and their role in Alzheimer's Disease for 24 years, and discovered 20 years ago that the presence of tau tangles is highly correlated with disease progression. In their view, amyloid plaque development, which has taken up most of the research attention so far, is poorly linked to dementia and is actually just a feature of normal ageing.

Wischik discovered the fact that methylthioninium chloride (MTC) could dissolve tau protein filaments when he accidentally put a drop of it in a test tube holding tau protein nearly 20 years ago, said a BBC report. MTC is more commonly known to scientists as a blue dye in laboratories. Since then, MTC has also been shown to block the toxic effects of tau tangles in cells, leading to cognitive and behavioral improvements in animals.

For this study, Wischik and his team carried out a 24 week, double blind, randomized, parallel design trial of orally administered MTC at three different doses (30, 60 and 100 mg) taken three times a day. The participants were 321 Alzheimer's patients being treated at 17 centers in the UK and Singapore. This phase was then followed by 60 weeks of further blinded active treatment.

The patients in the control group received placebo for the first 24 weeks, then a minimal dose of MTC after that.

The main aim of the trial was to compare the effects of the drug with placebo, as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog test) in patients with mild or moderate Alzheimer's.

A secondary aim was to find out if the drug was able to change the course of the disease over 19 months. The researchers also took SEPCT and PET scans of the participants' brains, at the start of the study (baseline) and at the end of the first phase (after 24 weeks of treatment).

The results showed that:

• At 24 weeks the moderate Alzheimer's patients on the 60 mg dose of MTC showed significant improvement in the cognition test compared to those on placebo (-5.5 ADAS-cog units, p = 0.0208).


• The placebo group of mild Alzheimer's patients did not show cognitive decline sufficiently significant to test the efficacy of MTC in the first 24 weeks.


• However, SPECT scans of the mild Alzheimer's patients after 24 weeks showed sufficient differences between the drug and placebo groups to demonstrate efficacy of MTC, said the researchers.


• For both mild and moderate Alzheimer's patients, MTC stabilized disease progression over 50 weeks.


• The overall effect size of MTC over this period was -6.8 ADAS-cog units versus a decline of 7.8 units in the placebo group (p < 0.0001), an effect that was also significant in the mild and moderate groups separately.


• A first approximation calculation showed that MTC at the 60 mg dose had a larger effect size at 50 weeks than at 24 weeks, suggesting there was an effect on the rate of cognitive decline (p = 0.0014).


• Another calculation, a mixed effect slope analysis, confirmed this, revealing an 81 per cent "reduction of long run rate of progression of decline over 50 weeks" (p < 0.0001).


• The final analysis, at the end of the 84th week of the trial, confirmed the long term effect of the 60 mg dose on participants remaining on MTC.


• The researchers said that the apparent decline in the MTC patients was still "not significantly different from baseline at final assessment, whereas there was significant decline in the other study arms".

Wischik concluded that:

"Our results appear to meet the draft EMEA clinical guidelines for disease-modifying therapy, supported by SPECT and PET evidence of efficacy in brain regions heavily affected by tau pathology."

The SPECT and PET brain images confirmed the clinical trial results, said the researchers. SPECT images measure the flow of blood in areas of the brain (regional cerebral blood flow or rCBF), a reliable measure of brain cell activity. Scans of patients on the 60 mg dose of MTC showed none of the rCBF decline visible in scans of patients on placebo, and the effect was greatest in those parts of the brain that suffer the earliest and the worst accumulations of tau protein, the hippocampus and the entorhinal cortex.

Wischik said that the trial was the first "disease-modifying Alzheimer's therapy that has attained its primary, pre-specified cognitive efficacy target". It is also the first trial to show that blocking tau protein aggregation may be a viable treatment:

"We now need to confirm this in a larger Phase III trial," he added, explaining in a separate statement that:

"With the world population ageing globally and the enormous burden on health services and economies worldwide, we urgently need to confirm our findings in a larger trial with a view to making this treatment available as soon as possible."

The World Health Organisation (WHO) predicts that by 2050 there will be more than 1 billion people over the age of 65, and Wischik said about half of them will have tau tangles in their brains, emphasizing the urgent need to develop new treatments not only to stop, but also to prevent them forming in the first place.

The version of MTC that was used in the trial is branded as remberTM, whose medical use is being patented by TauRx Therapeutics for the treatment and prevention of Alzheimer's.

As well as testing remberTM further in a phase 3 trial on Alzheimer's Disease, TauRx are planning to test its effectiveness as a treatment for Parkinson's Disease, because the drug also targets the synuclein fibres that accumulate in brains of people with this disease.

Source: ICAD, TauRx, BBC.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
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